This invention relates to new camptothecin analogues useful for the treatment of cancer, to intermediates useful for their synthesis, and to methods of preparing the analogues and intermediates.
Camptothecin (1) is a pentacyclic alkaloid possessing a fused quinoline in rings A and B, a pyrroline in ring C, an .alpha.-pyridone in ring D, and a six-membered lactone in ring E, and was first isolated from Camptotheca acuminata (Nyssaceae), a tree native to southern China (Wall, et al., J. Amer. Chem. Soc., 88, 3888-3890 (1966)). Promising antitumor and antileukemic activity and extreme rarity of the compound in nature (present in stem bark at abundances of about 0.01% by weight) have motivated extensive studies directed toward the total synthesis of camptothecin as well as the design of analogues intended to exhibit greater activity and lower toxicity than camptothecin itself. The results of these efforts have been comprehensively reviewed (C. R. Hutchinson, Tetrahedron, 37, 1047-1065 (1981); A. G. Schultz, Chemical Rev., 73, 385-405 (1973)).
Mechanistic studies of the biological action of camptothecin have pointed to the enzyme topoisomerase I as the main intracellular target of the compound. By binding to and stabilizing a covalent DNA-topoisomerase I complex in which a strand of DNA is broken (R. P. Hertzberg, et al., J. Med. Chem., 32, 715 (1989); W. D. Kingsbury, et al., J. Med. Chem., 34, 98 (1991)), it is believed, camptothecin damages DNA and strongly inhibits the synthesis of nucleic acids in cancer cells. A structure-activity correlation for camptothecin analogues has been established between the anti-cancer activity of an analogue and its ability to stabilize the DNA-topoisomerase I complex. Adding further weight to this belief, cell lines which are resistant to camptothecin have been determined to contain a mutated form of topoisomerase I (R. S. Gupta, et al., Cancer Res., 48, 6404 (1988)).
High toxicity and low solubility have diminished the clinical utility of camptothecin, stimulating a search for derivatives which transcend these limitations. Numerous analogues have been prepared by methods described in previous disclosures. None of these methods, however, offer a general approach for preparing camptothecin analogues with highly variable ring substitution patterns. For example, Miyasaka, et al. (U.S. Pat. No. 4,399,282, issued Aug. 16, 1982), disclose camptothecin analogues substituted by an alkyl, aralkyl, alkoxycarbonyl, or alkoxyalkyl group exclusively in the 7-position, while J. C. Boehm, et al. (U.S. Pat. No. 5,004,758, issued Apr. 2, 1991), disclose camptothecins substituted at positions 9 and 10, and Miyasaka, et al. (U.S. Pat. no. 4,473,692, issued Sep. 25, 1984) provide compounds with certain groups located at positions 5, 7, and 10, but not otherwise. Because of the sparing solubility of camptothecin in many organic solvents, and because of the special characteristic of camptothecin that the aromatic rings lack sufficient reactivity to afford ring-substituted analogues, the usual electrophilic ring substitution reactions cannot be performed productively on the parent structure. As a result, few direct methods exist for the preparation of potentially valuable substitution patterns. In one exceptional instance, nitration has been effected by Chinese workers (P. Pei-chuang, et al., Hau Hsueh Hsueh Pao, 33, 71 (1975); Chem. Abstr., 84, 115629p (1975)) at the 12-position under severe conditions (nitric acid/sulfuric acid) at the 9-position of a 10,11-methylenedioxycamptothecin (M. E. Wall, et al., U.S. Pat. No. 5,049,668, issued Sep. 17, 1991), and at the 10-position by proceeding through a tetrahydrocamptothecin intermediate followed by subsequent re-oxidation (Miyasaka, et al., U.S. Pat. No. 4,473,692, issued Aug. 25, 1984), thereby allowing access to a range of substitution but at the cost of starting from the rare native camptothecin or its analogues.
Chemical modifications of the A, B, or C rings are of greatest therapeutic interest based on previous structure-function studies. However, while most alterations in the D and E rings have resulted in depressed biological activity, certain modifications of these rings have been achieved without losing activity, as disclosed in U.S. Pat. No. 3,894,029, issued Jul. 18, 1975, U.S. Pat. No. 4,031,098, issued Jun. 21, 1977, U.S. Pat. No. 4,914,205, issued Apr. 3, 1990, and U.S. Pat. No. 4,943,579, issued Jul. 24, 1990. The present invention allows simultaneous substitution changes in all rings of camptothecin.
While several syntheses of camptothecin have been disclosed in prior art (for example, E. J. Corey, et al., J. Amer. Chem. Soc., 40, 2140 (1975); J. C. Bradley, et al., J. Org. Chem., 41, 699 (1976); G. Stork, et al., J. Amer. Chem. Soc., 93, 4074 (1971); E. Winterfeld, et al., Angew. Chem., 84, 265 (1972)), the present approach offers the combined advantages of good preparative yield. a minimum number of reaction steps, and synthetic flexibility in the design of derivative analogues of camptothecin. Certain embodiments of the present invention allow synthetic yields of camptothecin as high as 39% from abundantly available tricyclic pyridones. Because of the possibility of obtaining a large variety of analogues, and given the intense anti-cancer activity of the parent structure, the present invention makes feasible the large-scale synthesis of a many new anti-cancer pharmaceuticals with more desirable chemical and clinical properties. Valuable enhancements in properties include improved solubility, bioavailability, and anticancer activity. The present invention therefore provides methods which represent a potentially significant advance for cancer chemotherapy.